This project is aimed at understanding aspects of the pathogenesis of herpes simplex virus (HSV) infection in the nervous system including the mechanism by which this neurotropic virus is regulated within neurons during acute, latent, and reactivated infections. A further objective is to understand the relationship between HSV and disease. During FY 1991 studies were initiated to develop transgenic mouse models to investigate the mechanism by which HSV-1 replication is regulated in the nervous system. In initial experiments, expression of the mouse homeodomain protein, Hox 1.3, in transgenic mice resulted in 1,000-fold increased replication of HSV-l in the brain. After intracerebral inoculation, transgenic mice were at least lOO-fold more susceptible to the lethal effects of HSV-1 than nontransgenic littermates. Hox l.3 transgenics were also markedly more susceptible when virus was inoculated by corneal and intraperitoneal routes. Embryo fibroblasts derived from transgenics yielded 3O-5O-fold more virus than corresponding cells from nontransgenics after inoculation with HSV-l. These experiments represent the first demonstration that a single host gene can significantly increase host susceptibility to an important neurotropic virus. It was also discovered that HSV-1 can replicate in the mouse lens and cause cataracts following intracorneal inoculation.